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In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca 2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into “responder” and “non-responder”. By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4 . We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5 . CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder ( ERN1, IGFBP3, IGFBP5 ) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.

In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1[alpha]) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1[alpha]/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFN[gamma] signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1[alpha]- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1[alpha] gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1[alpha] deletion lose the integrity of the gene connectivity characteristic of regulated IRE1[alpha]-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1[alpha]/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

In the tumor microenvironment local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the upregulation of IL-6, IL-23, Arginase1, as well as surface expression of CD86 and PD-L1. Macrophages in which the IRE1α/Xbp1 axis is blocked pharmacologically or deleted genetically have significantly reduced polarization, and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNASeq analysis showed that bone marrow derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

A key issue distinguishing prominent evolutionary models of human life history is whether prolonged childhood evolved to facilitate learning in a skill- and strength-intensive foraging niche requiring high levels of cooperation. Considering the diversity of environments humans inhabit, children’s activities should also reflect local social and ecological opportunities and constraints. To better understand our species’ developmental plasticity, the present paper compiled a time allocation dataset for children and adolescents from twelve hunter-gatherer and mixed-subsistence forager societies ( n  = 690; 3–18 years; 52% girls). We investigated how environmental factors, local ecological risk, and men and women’s relative energetic contributions were associated with cross-cultural variation in child and adolescent time allocation to childcare, food production, domestic work, and play. Annual precipitation, annual mean temperature, and net primary productivity were not strongly associated with child and adolescent activity budgets. Increased risk of encounters with dangerous animals and dehydration negatively predicted time allocation to childcare and domestic work, but not food production. Gender differences in child and adolescent activity budgets were stronger in societies where men made greater direct contributions to food production than women. We interpret these findings as suggesting that children and their caregivers adjust their activities to facilitate the early acquisition of knowledge which helps children safely cooperate with adults in a range of social and ecological environments. These findings compel us to consider how childhood may have also evolved to facilitate flexible participation in productive activities in early life.

Aspects of human life history and cognition, such as our long childhoods and extensive use of teaching, theoretically evolved to facilitate the acquisition of complex tasks. The present paper empirically examines the relationship between subsistence task difficulty and age of acquisition, rates of teaching, and rates of oblique transmission among Hadza and BaYaka foragers from Tanzania and the Republic of Congo. We further examine cross-cultural variation in how and from whom learning occurred. Learning patterns and community perceptions of task difficulty were assessed through interviews. We found no relationship between task difficulty, age of acquisition, and oblique transmission, and a weak but positive relationship between task difficulty and rates of teaching. While same-sex transmission was normative in both societies, tasks ranked as more difficult were more likely to be transmitted by men among the BaYaka, but not among the Hadza, potentially reflecting cross-cultural differences in the sexual division of subsistence and teaching labor. Further, the BaYaka were more likely to report learning via teaching, and less likely to report learning via observation, than the Hadza, possibly owing to differences in socialization practices.

Recent studies have proposed that social norms play a key role in motivating human cooperation and in explaining the unique scale and cultural diversity of our prosociality. However, there have been few studies that directly link social norms to the form, development and variation in prosocial behaviour across societies. In a cross-cultural study of eight diverse societies, we provide evidence that (1) the prosocial behaviour of adults is predicted by what other members of their society judge to be the correct social norm, (2) the responsiveness of children to novel social norms develops similarly across societies and (3) societally variable prosocial behaviour develops concurrently with the responsiveness of children to norms in middle childhood. These data support the view that the development of prosocial behaviour is shaped by a psychology for responding to normative information, which itself develops universally across societies. In a cross-cultural study of eight diverse societies, House et al. provide evidence that links societal variation in prosociality to the development of a universal psychology for responding to social norms.

The function of dreams is a longstanding scientific research question. Simulation theories of dream function, which are based on the premise that dreams represent evolutionary past selective pressures and fitness improvement through modified states of consciousness, have yet to be tested in cross-cultural populations that include small-scale forager societies. Here, we analyze dream content with cross-cultural comparisons between the BaYaka (Rep. of Congo) and Hadza (Tanzania) foraging groups and Global North populations, to test the hypothesis that dreams in forager groups serve a more effective emotion regulation function due to their strong social norms and high interpersonal support. Using a linear mixed effects model we analyzed 896 dreams from 234 individuals across these populations, recorded using dream diaries. Dream texts were processed into four psychosocial constructs using the Linguistic Inquiry and Word Count (LIWC-22) dictionary. The BaYaka displayed greater community-oriented dream content. Both the BaYaka and Hadza exhibited heightened threat dream content, while, at the same time, the Hadza demonstrated low negative emotions in their dreams. The Global North Nightmare Disorder group had increased negative emotion content, and the Canadian student sample during the COVID-19 pandemic displayed the highest anxiety dream content. In conclusion, this study supports the notion that dreams in non-clinical populations can effectively regulate emotions by linking potential threats with non-fearful contexts, reducing anxiety and negative emotions through emotional release or catharsis. Overall, this work contributes to our understanding of the evolutionary significance of this altered state of consciousness.

Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19–75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age < 50; 35% for age 50–60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = −0.29, P < 0.01) and Executive Functioning (r = −0.24, P < 0.01), whereas greater age was associated with poorer Memory performance only (r = −0.33, P < 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes.

This large outbreak of foodborne salmonellosis demonstrated the complexity of investigating outbreaks linked to poultry products. The outbreak also highlighted the importance of efforts to strengthen food safety policies related to Salmonella in chicken parts and has implications for future changes within the poultry industry. To investigate a large multistate outbreak of multidrug resistant Salmonella Heidelberg infections. Epidemiologic and laboratory investigations of patients infected with the outbreak strains of Salmonella Heidelberg and traceback of possible food exposures. United States. Outbreak period was March 1, 2013 through July 11, 2014. A case was defined as illness in a person infected with a laboratory-confirmed Salmonella Heidelberg with 1 of 7 outbreak pulsed-field gel electrophoresis (PFGE) XbaI patterns with illness onset from March 1, 2013 through July 11, 2014. A total of 634 case-patients were identified through passive surveillance; 200/528 (38%) were hospitalized, none died. Interviews were conducted with 435 case-patients: 371 (85%) reported eating any chicken in the 7 days before becoming ill. Of 273 case-patients interviewed with a focused questionnaire, 201 (74%) reported eating chicken prepared at home. Among case-patients with available brand information, 152 (87%) of 175 patients reported consuming Company A brand chicken. Antimicrobial susceptibility testing was completed on 69 clinical isolates collected from case-patients; 67% were drug resistant, including 24 isolates (35%) that were multidrug resistant. The source of Company A brand chicken consumed by case-patients was traced back to 3 California production establishments from which 6 of 7 outbreak strains were isolated. Epidemiologic, laboratory, traceback, and environmental investigations conducted by local, state, and federal public health and regulatory officials indicated that consumption of Company A chicken was the cause of this outbreak. The outbreak involved multiple PFGE patterns, a variety of chicken products, and 3 production establishments, suggesting a reservoir for contamination upstream from the production establishments. Sources of bacteria and genes responsible for resistance, such as farms providing birds for slaughter or environmental reservoir on farms that raise chickens, might explain how multiple PFGE patterns were linked to chicken from 3 separate production establishments and many different poultry products.